The current anti-cancer drugs, such as cisplatin, are also toxic to normal, healthy cells. The relatively high doses that need to be administered to a patient cause severe side effects. Enhanced selectivity by targeting cancer cells would be beneficial for the therapeutic index and the life quality of the patient.
In radionuclide therapy use is made of the metabolic accumulation of a radiopharmaceutical to deliver a therapeutic radiation dose to a tissue. The critical factor for successful radionuclide therapy is target tissue accumulation in relation to normal tissue, which is in the range of 5 to 100 in all methods known so far. An exception to this is the very successful iodine metabolic therapy of thyroid disease. Due to the low ratio of accumulation in target to normal tissue the radiation burden to the patient's normal tissues is often relatively high. A need thus exists for a way to specifically deliver the radionuclide to the target tissue.
An interesting candidate compound that may lead to site specific uptake is vitamin B12. Fast proliferating cancer cells are so-called high B12 consumers. This very high demand makes vitamin B12 a potential “trojan horse” for delivering therapeutic agents.
Cyanocobalamin (vitamin B12) is well known and its chemistry has been comprehensively reviewed. Many patents and publications exist for the derivatization of vitamin B12 at the cobalt, corrin ring or the ribose moiety. Some of these vitamin B12 derivatives have been proposed for application in cancer therapy or diagnosis but none have entered the market yet.
US2004/224921 for example relates to fluorescent cobalamins comprised of a fluorescent, phosphorescent, luminescent or light-producing compound that is covalently linked to cobalamin. These fluorescent cobalamins can be used as diagnostic and prognostic markers to distinguish cancer cells and tissues from healthy cells and tissues, and to determine if an individual will respond positively to chemotherapy using cobalamin-based therapeutic bioconjugates. The fluorescent, phosphorescent or light-producing compounds can be covalently linked to the cobalt atom, the corrin ring, or the ribose moiety of cobalamin. This type of derivatization is also described for non-fluorescent compounds.
Derivatization directly at the cobalt leads to a compound that retains more than 90% of the vitamin B12 activity. Derivatization at that position is thus an obvious choice. However, these compounds have also disadvantages. For example, cobalt alkylated compounds are light sensitive.
Derivatizations at the ribose or at positions on the corrin framework have the drawback of not being cleavable, thus influencing the biological behaviour of vitamin B12 significantly.
A need therefore exists for a drug which can be used for the diagnosis and treatment of cancer, which does not carry severe side effects nor leads to a high radiation burden.